Derangements of iron metabolism are among the most common, and least understood, of human ills. Each of the proposed research projects is concerned with one or more aspects of iron metabolism in mammalian cells. Research plans range in score from studies of cellular iron uptake to molecular dynamics of transferring and employ technologies spanning protein engineering to laser spectroscopy. Major thrusts of the component projects are: Project 1: Mechanisms of cellular iron uptake from transferring focuses on cellular iron acquisition from transferrin by receptor-independent routes, and also includes studies of transferrin-transferrin receptor interactions (in collaboration with Project 2) and relationship of iron binding by transferrin to conformational changes in the protein (in collaboration with Project 5). Project 2: Functional domains of the transferring receptor inquires into the interactions of transferrin receptor with transferrin (in collaboration with Project 1) and functional interactions of the hemochromatosis gene product and the transferrin receptor. Project 3: Uptake of transferrin & non-transferrin bound F by SFT seeks to study the regulation of cellular iron uptake by SFT (stimulated of iron transport) newly discovered by the P.I., in a project interacting with all other projects of this proposal. Project 4: Role of copper in iron metabolism examines the long-known but little understood connections between iron and copper metabolism in mammalian cells, and in particular the role of copper dependent ferroxidases in iron transport. Project 5: Structure, function and dynamics in transferrin investigates the molecular mechanisms through which the uptake and release of iron and other metals by transferrin are modulated by physiological factors.